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The Impact of HLA-C Matching on Donor Identification Rates in a European-Caucasian Population

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      Abstract

      The degree of HLA concordance with the patient has long been known to be the major donor-related prediction factor for the success of hematopoietic stem cell transplantations and, with the progress of HLA typing technology, selection criteria became more stringent with regard to the recommended loci and resolution. A late refinement was HLA-C matching, which gained broader acceptance only after the turn of the millennium. The enormous HLA polymorphism has always necessitated registries with a large number of donors in order to be able to provide well-matched donors to a substantial fraction of patients. Using a biostatistical approach, we investigated the impact of adding HLA-C at low or high resolution as a supplementary matching criterion on some key parameters in donor provision for a European-Caucasian population. Starting point is donor selection based on allele level matching for HLA-A, -B, -DRB1, and, optionally, HLA-DQB1. Without typing for HLA-C, 68% of the donors selected based on matching for HLA-A, -B, -DRB1, and -DQB1 at high resolution will also match for HLA-C, 29% will have a single and only 3% will have two HLA-C alleles different from the patient. In order to provide the same fraction of patients with a fully matched donor, a registry would have to be about twice the size if HLA-C is considered in addition to the four other loci, with the exact factor increasing with the registry’s size. If the provision of donors with up to a single allele mismatch is considered, this factor doubles due to the strong linkage between HLA-B and -C. These figures only change slightly when HLA-DQB1 is completely ignored or HLA-C matching is only considered at low resolution. Our results contribute to quantifying the medical and economic impact of the progress in donor selection algorithms.

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      Hematopoietic stem-cell transplantation.

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        High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.

        The relative importance of various human leukocyte antigen (HLA) loci and the resolution level at which they are matched has not been fully defined for unrelated donor transplantation. To address this question, National Marrow Donor Program data from 3857 transplantations performed from 1988 to 2003 in the United States were analyzed. Patient-donor pairs were fully typed for HLA-A, -B, -C, -DRB1, -DQB1, -DQA1, -DPB1, and -DPA1 alleles. High-resolution DNA matching for HLA-A, -B, -C, and -DRB1 (8/8 match) was the minimum level of matching associated with the highest survival. A single mismatch detected by low- or high-resolution DNA testing at HLA-A, -B, -C or -DRB1 (7/8 match) was associated with higher mortality (relative risk, 1.25; 95% CI, 1.13-1.38; P < .001) and 1-year survival of 43% compared with 52% for 8/8 matched pairs. Single mismatches at HLA-B or HLA-C appear better tolerated than mismatches at HLA-A or HLA-DRB1. Mismatching at 2 or more loci compounded the risk. Mismatching at HLA-DP or -DQ loci and donor factors other than HLA type were not associated with survival. In multivariate modeling, patient age, race, disease stage, and cytomegalovirus status were as predictive of survival as donor HLA matching. High-resolution DNA matching for HLA-A, -B, -C, and -DRB1 alleles is associated with higher rates of survival.
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          Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.

          Outcome of unrelated donor marrow transplantation is influenced by donor-recipient matching for HLA. Prior studies assessing the effects of mismatches at specific HLA loci have yielded conflicting results. The importance of high-resolution matching for all HLA loci has also not been established. We therefore examined the effects of HLA matching (low or high resolution or both) on engraftment, graft-versus-host disease (GVHD), and mortality in 1874 donor-recipient pairs retrospectively typed at high resolution for HLA-A, -B, -C, -DRB1, -DQ, and -DP. Mismatches at HLA-A, -B, -C, and -DRB1 each had similar adverse effects on mortality. Only HLA-A mismatches demonstrated significant adverse effects on GVHD. These adverse effects on outcome were more evident in transplants with low-resolution versus only high-resolution mismatches. Mismatches for HLA-DQ or -DP did not significantly affect outcome. When high-resolution mismatches at HLA-A, -B, -C, and -DRB1 were considered together, adverse effects on survival and GVHD were observed. We therefore conclude that matching for HLA-C should be incorporated into algorithms for unrelated donor selection. High-resolution mismatches at HLA-A, -B, -C, and -DRB1 adversely affect outcome, but less so than low-resolution mismatches. When clinical circumstances allow, high-resolution class I typing may help optimize donor selection and improve outcome.
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            Author and article information

            Affiliations
            1Zentrales Knochenmarkspender-Register Deutschland (ZKRD) , Ulm, Germany
            Author notes

            Edited by: Antoine Toubert, Université Paris Diderot, France

            Reviewed by: Ralf Dressel, University Medical Center Göttingen, Germany; Nicolas Dulphy, Université Paris Diderot, France; Alain Haziot, Institut National pour la Santé et la Recherche Médicale (INSERM), France

            *Correspondence: Carlheinz R. Müller, Zentrales Knochenmarkspender-Register Deutschland (ZKRD), POB 4244, Ulm 89032, Germany e-mail: carlheinz.mueller@ 123456zkrd.de

            This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology.

            Contributors
            URI : http://frontiersin.org/people/u/172421
            URI : http://frontiersin.org/people/u/172430
            Journal
            Front Immunol
            Front Immunol
            Front. Immunol.
            Frontiers in Immunology
            Frontiers Media S.A.
            1664-3224
            04 September 2014
            15 October 2014
            2014
            : 5
            4197773 10.3389/fimmu.2014.00501
            Copyright © 2014 Eberhard and Müller.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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            Figures: 2, Tables: 1, Equations: 1, References: 36, Pages: 6, Words: 4229
            Categories
            Immunology
            Original Research

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